The pituitary gland, a very small gland that lies at the base of the brain, has been labeled the master gland of the human body. Physiologically, the pituitary is divided ino two distinct portions, the anterior pituitary and the posterior pituitary. Six life-controlling hormones, in addition to several less important hormones, are secreted by the anterior pituitary, while only two generally recognized important hormones are secreted by the posterior pituitary.
The principal hormones secreted by the anterior pituitary are: (1) Growth hormone, which promotes growth of the animal by effects on the metabolic functions throughout the body, especially protein formation; (2) Adrenocorticotropin which controls the secretion of the principal adrenocortical hormones, which hormones in turn affect the metabolism of glucose, proteins, and fats; (3) Thyroid-stimulating hormone controls the rate of secretion of thyroxine by the thyroid gland, and thyroxine in turn controls the rates of most chemical reactions in the entire body; (4) Prolactin promotes the development of the mammary glands and milk production; (5) Follicle-stimulating hormone; and (6) Luteinizing hormone. The latter two hormones control the growth of the gonads as well as their reproductive activities.
The two principal hormones secreted by the posterior pituitary are (1) Antiduretic hormone and (2) Oxytocin. The antiduretic hormone controls the rate of water excretion into the urine controlling thereby the water balance of the body tissue. Oxytocin performs two main functions, brings about delivery of milk from glands of the breast to the nipples during sucking and, it is believed, helps in the delivery of babies at the end of the gestation periods.
The anterior pituitary is a highly vascular gland with an extensive capillary system among its glandular cells and is directly connected to the hypothalamus of the brain by hypophyseal stalk through which the vascular system of the hypothalamus is directly connected with the vascular system of the anterior pituitary.
While it is well known that the hypothalamus produces releasing and inhibitory factors that control the secretions of the anterior pituitary, only recently has it become known that special neurons in the hypothalamus synthesize and secrete these releasing and inhibitory factors. The hypothalamic factors secreted are immediately absorbed into the vascular system of the hypothalamus flowing therethrough directly to the anterior pituitary gland. It is known that for each hormone synthesized by the anterior pituitary there is a corresponding hypothalamic releasing factor; and more important, for some of the anterior pituitary hormones, there is also a corresponding hypothalamic inhibitory factor. While the releasing factor is the most important factor for most of the anterior pituitary hormones, for prolactin, it is the hypothalamic inhibitory factor which exerts the important control.
The most important hypothalamic releasing and inhibitory factors corresponding to the anterior pituitary hormones described hereinabove are: (1) Thyroid-stimulating hormone releasing factor (TRH or TRF) which causes release of thyroid stimulating hormone; (2) Corticotropin releasing hormone (CRH or CRF) which causes release of adrenocorticotropin; (3) Growth (Somatotrophin) hormone releasing factor (GRH or GRF) which causes release of growth hormone; Growth (Somatostatin) hormone inhibiting factor (GIF or SRIF); (4) Luteinizing hormone releasing factor (LRH or LRF) which causes release of luteinizing hormone; (5) Follicle-stimulating hormone releasing factor (FRH or FRF) which causes release of follicle stimulating hormone; (6) Prolactin inhibitory factor (PIH or PIF) which causes inhibition of prolactin secretion; Prolactin release factor (PRF); and Melanocyte hormone release factor (MRH or MRF), Melanocyte inhibiting factor (MIH or MIF). For simplicity, the hypothalamic produced releasing and/or inhibitory agents will be referred to hereinafter by the initials TRF, CRF, GRF, GIF, LRF, FRF, PIF, PRF, MRF and MIF.
In addition to the aforementioned releasing and inhibitory factors, it is believed that an additional control on the anterior pituitary hormones is exerted by opiate peptides such as enkephalins or .beta.-endorphin, which exercise their influence on the circulating levels of growth hormone, luteinizing hormone, and prolactin, particularly during sexual maturation. The opiate peptides are well-known for their property of exhibiting analgesic activity, presumably by acting at highly specific opiate receptor sites on the surface of certain neurons. Opiate peptides have been found principally in the brain, particularly in the cells of the limbic system which is associated with the arousal of emotion in humans and with smelling in lower vertebrates. It has been postulated that opiate peptide receptors in this area may be responsible for the euphoria-producing characteristics of the opiate drugs.
While the mechanism by which the opiate peptides regulate the anterior pituitary hormones is not entirely clear, it is believed that these peptides exert their influence by acting at certain receptor sites in the central nervous system to indirectly stimulate or inhibit release of anterior pituitary hormones. The hypothalamic releasing and inhibitory factors, however, appear to be released by hypothalamic neurons in response to appropriate stimuli, and are transported to specific receptor sites in the pituitary gland which interact with the specific factor to evoke the appropriate biological response.
The hypothalamic releasing and inhibitory factors and opiate polypeptides relevant to the invention are carboxyl terminal polypeptides.
The naturally occurring thyroid-stimulating hormone releasing factor (TRF) is the tripeptide L-pyroglutamyl-L-histidyl-L-prolinamide. Methods of synthesizing the compound are well-known. The structure of this compound is: ##STR3##
The secretion of TSH by the pituitary gland is normally regulated by an interaction between TRF, which stimulates TSH release, and thyroid hormones which inhibit it. TRF is a useful diagnostic compound for testing pituitary TSH reserve and for distinguishing pituitary from hypothalamic hypothyroidism (forms of thyroid malfunction). The TSH pattern of response to the administration of TRF may also be useful for studying thyroid function. Patients with hyperthyroidism (increased thyroid gland activity) or patients given T.sub.3 do not respond to TRF. Patients with primary hypothyroidism due to thyroid disease (high TSH) show exaggerated and prolonged response to TRF. Patients with pituitary hypothyroidism (secondary hypothyroidism) with low TSH levels fail to show a rise in plasma TSH after TRF administration. Patients with tertiary hypothyroidism due to hypothalamic disease show response to TRF.
The physiological influence of TRF on the reproductive behavior in mammal is well-documented, for example, administration of TRF in a therapeutically effective dosage prevents ovulation and subsequent elevation of serum progesterone. It is also known that administration of TRF, or certain pathological conditions which bring about an increased secretion or release of TRF by the hypothalamus also causes a marked increase in serum prolactin in mammals. It was subsequently discovered that an increase in TRF inhibits the secretion of the prolactin inhibitory factor (PIF) and there is now evidence that alterations in pituitary function are involved in tumor regression promoted by progesterone. Further, since TRF has been found in parts of the brain other than the hypothalamus and in other tissues such as intestine, it has been suggested that TRF may function as a neuro-secretory substance as well as a hormone releasing factor.
The luteinizing hormone releasing factor (LRF) has the established chemical decapeptide structure: EQU Pyroglu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2
There is strong controversy concerning whether or not there is actually a follicle releasing hormone separable from luteinizing releasing factor. Since LRF promotes release of follicle stimulating hormone (FSH), it is also known as FSH-RH/LH-RH. Analogs of the decapeptide have been prepared, some of which behave as LRF and others as LRF antagonist, however, no one molecule has been shown to promote a selective release of only one of the gonadotropins. LRH does promote LH synthesis and can elevate total LH content of the pituitary gland. Under physiological conditions the luteinizing, growth, and prolactin hormones are subjected to primarily negative feedback control involving the gonado steroids which depends upon the release of particular hormones and positive control from the hypothalamus.
The chemical structure of the growth hormone inhibitory factor (GIF) is a tetradecapeptide containing 14 amino acids and a disulfide bond with the following structure: ##STR4## Somatotrophic or growth hormone (GH) affects virtually every cell in the body and is released in response to quite a few body stimuli including stress. GRF is highly effective for bringing about the release of GH from the pituitary and elevations of GH in the plasma, while GIF reduces the generation of cyclic adenosine 3',5'monophosphate (cAMP) and blocks responses to agents which raise cAMP concentrations. In addition, GIF has been identified in many parts of the brain and influences behavior, inhibits release of TRF and blocks responses to TRF, inhibits secretion of prolactin and exerts a direct influence on both .alpha. and B cells of the pancreatic islets.
The control of prolactin secretion is predominantly inhibitory through the action of PIF, a small acid-soluble peptide. For the most part, prolactin-releasing activity is attributed to TRH. The neurotransmitter, dopamine, increases PIH activity in the portal blood of rats and decreases the release of prolactin. While other hormones, e.g. growth hormone, insulin, estrogen, and corticosteroid are also influential, prolactin is involved in the initiation and maintenance of lactation.
The chemical structure proposed for melanocyte hormone releasing factor (MRF) is a pentapeptide structure while the melanocyte inhibiting factor (MIF) is a tripeptide. MIF and some of its analogs have been reported to be active in inhibiting the oxotremorine-induced tremors which are believed to be similar in nature to those found in Parkinson's disease.
Two of the important opiate peptides are methionine enkephalin and leucine enkephalin, of the following respective structures:
(1) Tyr-Gly-Gly-Phe-Met PA1 (2) Tyr-Gly-Gly-Phe-Leu
Thus, in view of the multifaceted activity of the peptide hypothalamic releasing and inhibitory factors, and the opiate peptides, particularly the activity of these peptides as affecting the inhibition, release, or circulating levels of the anterior pituitary hormones, it is highly desirable to provide pituitary modulator compounds by which the activity of the releasing and inhibitory factors or opiate peptides may be regulated. Modulator compounds, acting as agonists or antagonists to the several hypothalamic factors or opiate peptides, are thus useful to modify the various effects of the anterior pituitary hormones.